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Abstract

Simple 46, XY gonadal dysgenesis syndrome, also called Swyer syndrome, is known as
pure gonadal dysgenesis. Individuals with the syndrome are characterized by 46, XY
karyotype and phenotypically female with female genital appearance, normal Müllerian
structures and absent testicular tissue. The condition usually first becomes apparent
in adolescence with delayed puberty and primary amenorrhea due to the gonads have
no hormonal or reproductive potential. Herein, we report a case of dysgerminoma diagnosed
in a dysgenetic gonad of a 21-year-old patient with Swyer syndrome.

Keywords:

dysgerminoma; Swyer syndrome; 46, XY pure gonadal dysgenesis

Background

Doctor Swyer described two women whom had a 46, XY karyotype, tall stature, primary
amenorrhea, female external genitalia, normal vagina (albeit hypoestrogenised) and
cervix in 1955 [1]. Individuals with Swyer syndrome are phenotypically female with unambiguously female
genital appearance from birth and normal Müllerian structures. The patients usually
first become apparent in adolescence with delayed puberty and primary amenorrhea due
to the fact that the gonads have no hormonal or reproductive potential. Here, we report
a case of dysgerminoma diagnosed in a dysgenetic gonad of a 21-year-old patient with
Swyer syndrome.

Clinical history

A 21 years old patient with a history of primary amenorrhea, 46, XY karyotype, was
admitted to the hospital complainging of a low abdominal mass. The patient is 164
cm tall. She has breast development (tanner IV). The pubic hair distribution is adult
in type but decrease in total quantity. Her menstruation had not started until she
took estradiol valerate and medroxyprogesterone for 15 months, which was prescribed
by doctor in her 17 years old. In 19 years old, menstruation started, 6 days at intervals
of 23-40 days, blood is ruby-red, sometimes blood clot. However, menstruation disappeared
at the age of 20 because she stopped the pills. Chromosome analysis with fluorescence
in situ hybridization revealed 46, XY. Color doppler imaging (CDI) showed the uterus
was 3.22 × 5.19 × 2.80 cm, thickness of the endometrium was 0.19 cm thick. There was
a heterogenetic mixed echo (5.50 × 3.77 cm) behind the cervix. Laboratory investigations
showed CA125 was 11.53 U/ml (normal 0.00 ~ 35.00 U/ml), testosterone free (F-TEST)
was 34.5 pmol/L (normal 0.77 ~ 33.03 pmol/L), FSH was 56.70 mIU/ml, LH was 21.50 mIU/ml,
sex hormone binding globulin (SHBG) was 16.50 nmol/L (normal 18.0 ~ 114.0 nmol/L)
and carcino-embryonic antigen (CEA) was 0.55 ng/ml (normal 0 ~ 4.3 ng/ml). Exploratory
laparotomy was performed. Surgical findings: The uterus was small (3.0 × 5.0 × 2.0
cm). A 5.0 × 5.0 × 4.0 cm firm mass involved the right gonad with a smooth surface
and good mobility. The left gonad was aplasia, like streak and without follicle. The
bilateral fallopian tubes were slender. The serosa of the liver, the spleen and the
stomach were smooth. There was no obvious nodule in the omentum. The result of the
frozen section is malignant tumor of the ovary. Based on the agreement with the patient
and her family bilateral salpingoopherectomy and hysterectomy (BSOH) and lymph node
dissection were performed. Due to tumor was classified as stageIA, adjuvant therapy
was not commented. Written consent for publication was obtained from the patient.

Pathology

Gross

A 5.0 × 5.0 × 4.0 cm firm mass involved the right gonad, while the left gonad appeared
as streak gonad measuring 3.0 × 0.6 × 0.6 cm. The tumor was encapsulated with a smooth
surface. The cut surface of the tumor was solid, fleshy, lobulated and gray-yellow
(Figure 1A). The bilateral fallopian tubes were slender. The uterus was small (3.0 × 5.0 × 2.0
cm) and the endometrium was smooth. The left gonad was 2.0 × 0.6 × 0.6 cm and appeared
as streak gonad (Figure 1B).

Figure 1.The right gonad was a 5.0 × 5.0 × 4.0 cm firm mass, encapsulated, with gritty gray-yellow
cut surface. The cut surface of the tumor was solid, fleshy, lobulated and gray (A). The double
fallopian tubes were slender. The uterus was small (3.0 × 5.0 × 2. 0 cm) and the endometrium
was smooth. The left gonad was 2.0 × 0.6 × 0.6 cm and appeared as streak gonad (B).

Histology and Immunohistochemistry

The tumor and the other abscised tissues were fixed in 10% formalin and embedded in
paraffin. Several 4-μm sections were cut from each paraffin block, and one was stained
with HE (hematoxylin and eosin), the others were stained with IHC (immunohistochemistry).
Immunohistochemical staining was performed using the streptavidin-peroxidase system
(Ultrasensitive; MaiXin Inc., Fuzhou, China) according to the manufacturer's instruction.
Commercially available prediluted monoclonal antibodies against the following antigens
were employed: CK(cell keratin), CD30, PLAP (placental alkaline phosphatase), CD117
(all Thermo Fisher Scientific Inc., Fremont, CA, USA).

Results

Microscopically, the tumor in the right dysgentic gonad showed the typical features
of dysgerminoma. The tumor cells grouped themselves in well-defined nests separated
by fibrous strands infiltrated by lymphocytes. The tumor cell membrane was prominent.
The uniform, rounded tumor cells have clear to eosinophilic cytoplasm, and a central,
large, rounded or flattened nucleus that contains one or a few prominent nucleoli.
Calcification was seen (Figure 2A~B). No metastases were detected. Immunohistochemically, the tumor cells were positive
for PLAP, CD117, and CK, but negative for CD30. (Figure 2C~E)

Figure 2.The tumor cells grouped themselves in well-defined nests separated by fibrous strands
infiltrated by lymphocytes. The tumor cell membrane was prominent. The uniform, rounded tumor cells have clear
to eosinophilic cytoplasm, and a central, large, rounded or flattened nucleus that
contains one or a few prominent nucleoli. Calcification was seen(A, HE × 200 B, HE
× 400). Immunohistochemically, the tumor cells were positive for PLAP(C, × 400), CD117(D,
× 400), and CK(E, × 400), but negative for CD30.

The squamous cells of the cervix was normal, and lymphocytes infiltrated was seen
in the cervix tissue. (Figure 3A). The endometrium was in early proliferative phrase--thin surface epithelium; straight,
short, narrow glands and compact stroma (Figure 3B). The left streak gonad had ovarian-type stroma (fibrous gonad), no primordial ovarian
follicles and calcification was seen (Figure 3C). The fallopian tubes were slender and the tissue structure were normal (Figure 3D).

Figure 3.The squamous cells of the cervix was normal, and lymphocytes infiltrated was seen
in the cervix tissue (A HE × 100). The endometrium was in early proliferative phrase (B HE × 40). The left streak gonad
with ovarian-type stroma, no primordial ovarian follicles and calcification was seen
(C HE × 100). The tissue structure of the fallopian tubes were normal (D HE × 200).

Discussion

The Swyer syndrome, 46, XY gonadal dysgenesis, belongs to the category of sexual abnormality
[2]. The syndrome was complete/pure gonadal dysgenesis. The patients with 46, XY gonadal
dysgenesis are diagnosed in early adolescence with delayed pubertal development. The
patients' mesonephric ducts (Wolffian ducts) are in atrophy, paramesonephric ducts
(Müllerian ducts) develops to uterus, fallopian tubes and part of the vagina as a
result of lacking testosterone and inhibitor of Müllerian ducts. As expected they
show elevated gonadotropins, normal female levels of androgens, low levels of estrogens,
female external genitalia, uterus and fallopian tubes. Minimal breast enlargement
reflects peripheral aromatization of androgens. Both gonads display fibrous tissue
that vaguely resembles ovarian stroma but no follicles. The etiology of 46, XY pure
gonad dysgenesis is thought to be a shot arm Y chromosome deletion involving SRY (putative
testicular-determining factor gene), a mutation in other genes that leads to inhibition
of SRY function or mutation of SRY function [3].

Swyer syndrome should be differentiated from the following two female phenotype (karyotype
XY) syndrome. One is the familial syndrome of testicular feminization, the most common
type of male pseudohermaphroditism. It occurs in individuals with a normal male chromosome
constitution with an end-organ defect (androgen insensibility). It characterized by
the presence of several well-developed female secondary sex characteristics. Individuals
are found to have a vagina (not a true vagina, but like a small "cupule"), bilateral
cryptorchid testes but no uterus [4,5]. The other is true hermaphrodites, which may have ovotestes containing both ova and
immature seminiferous tubules or other combinations of ovary and testis [6,7].

In patients with gonadal dysgenesis, either "pure"(with a 46,XX or 46, XY karyotype)
or associated with the somatic features of Turner's syndrome (with a 45,XO karyotype),
both gonads are represented by a streak of fibrous tissue that vaguely resembles ovarian
stroma [8,9]. Previously thought these patients do not seem to have an increased incidence of
gonadal tumors [10]. But modern studies show patients with 46, XY pure gonadal dysgenesis are at a higher
risk of developing gonadoblastoma and dysgerminoma, and may occur even in young ages.
The incidence of Swyer syndrome is 1:100 000 [11,12]. A bilateral gonadectomy should be done especially by laparoscopy when a Swyer syndrome
is discovered in order to avoid the risk of malignant transformation. There is possibility
of pregnancy by oocyte donation in some countries if the uterus was not removed for
a malignant etiology.

In this report, we provide a case of dysgerminoma diagnosed in a dysgenetic gonad
of a 21-year-old patient with Swyer syndrome, who presented with primary amenorrhea
and infertility of five years duration. Karyotype was consistent with 46, XY (pure).
In our case, testosterone free was 34.5 pmol/L, sex hormone binding globulin was 16.50
nmol/L, and menstrual function was associated with estradiol valerate and medroxyprogesterone
prescribed by doctor. Estrogen and progestin sequential therapy supports female secondary
sex development in patients with gonadal dysgenesis. The patient did not have a bilateral
gonadectomy after knowing she has a 46, XY caryotype because she wanted to be pregnant
and did not believe she had the risk of suffering from malignent of ovary. It is necessary
to take the familial screening of Swyer syndrome cases. As a malignant germ cell tumor
of the ovary, dysgerminoma can be found either in a pure form or mixed with other
germinal elements. Therefore in premenarchal patients with a pelvic mass, the karyotype
should be determined.

Differential diagnosis for dysgerminoma include diffuse large B cell lymphoma, poorly
differentiated carcinoma, embryonal carcinoma and gonadoblastoma. Coexistence of dysgerminoma
and gonadoblastoma is seen in about 50% of cases [13]. Histologic appearance of gonadoblastoma may be altered by hyalinization, calcification,
and/or overgrowth of a malignant germ cell element predominantly dysgerminoma. Maleki
et al. reported a case of dysgerminoma and gonadoblastoma in a dysgenetic gonad on
a touch preparation that described cytomorphologic findings of both neoplasms [14].

About 65% of dysgerminomas are stage I at diagnosis. About 85 ~ 90% of stage I tumors
are confined to one ovary; 10 ~ 15% are bilateral. Dysgerminoma is the only germ cell
malignancy that has this significant rate of bilaterality, other germ cell tumors
being rarely bilateral. The treatment of patient with early disgerminoma is resection
of the primary lesion and proper surgical staging. Chemotherapy and/or radiotherapy
are administered to patients with metastases. In patients whose contralateral ovary
has been preserved, some disease can develop in 5 ~ 10% of the retained gonads over
the next 2 years [15].

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

YH analyzed the data and wrote the manuscript as a major contributor. YW, QL and SD
contributed to management of the patient. AH and EW carried out the histopathological
evaluation and helped to write manuscript. All authors have read and approved the
final manuscript.

Acknowledgements

We wish to thank the colleagues in the Laboratory of Hematology of the First Affiliated
Hospital of China Medical University. Special thanks to Dr. Wang Yazhu and Dr. Liang
ying for the chromosomal analysis.